Metformin and insulin sensitivity -
While extrapolating this information to patients with T2DM may need further clinical studies, it is likely that lack of hypoglycemia in patients with T2DM treated with metformin is explained by enhanced hepatic glucose production due to increased glucagon secretion.
The study also shows that metformin reduces insulin secretion, which may reflect lesser need of insulin since insulin sensitivity is enhanced by metformin. Konopka AR, et al. Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes.
Cell Reports. This content does not have an English version. This content does not have an Arabic version. Metformin revisited. April 11, Chemical structure for metformin Enlarge image Close. Chemical structure for metformin Chemical structure for metformin 1,1-dimethylbiguanide; C4H11N5.
Maintenance of normal blood glucose concentrations Enlarge image Close. Maintenance of normal blood glucose concentrations Maintenance of normal blood glucose concentrations in individuals with prediabetes during treatment with metformin.
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Financial Services. Community Health Needs Assessment. For inclusion and exclusion criteria see Figure 1. All clinical measurements were performed in the pediatric outpatient clinics or day-care wards of these hospitals; the fitness tests were performed at the physical therapy outpatient clinic of the St Antonius Hospital and at the Sports Medical Centre of the Jeroen Bosch Hospital.
From the younger children, oral consent was obtained. All procedures were in accordance with the Declaration of Helsinki and the Medical Research Involving Human Subjects Act WMO of the Netherlands.
Consecutive study numbers for eligible participants corresponding with the randomization code and medication number for example, study number 1, corresponds with randomization number 1 and medication number 1 were allocated.
The randomization schedule in blocks of 20 per study centre was generated by the department of Clinical Pharmacy of the St Antonius Hospital, using PASW Statistics Both subjects and study staff were blinded during the month treatment period.
The randomization code was kept secured in the department of Clinical Pharmacy. The blind was not broken for any of the participants.
For ΔHOMA-IR, a group sample size of 60 participants per group was found to detect a difference of 1. Subjects were advised to take the medication during or after breakfast and dinner.
In case of gastro-intestinal complaints, the dosage was reduced to the last well-tolerated dose. After symptoms had disappeared, the dosage was again increased to the maximum of two tablets twice daily, if tolerated. To estimate medication compliance, pill counts were performed on returned medication packages during each hospital visit every 3 months.
Physical training by a physical therapist was offered twice weekly to all participants. During the monthly phone calls and three monthly visits participants were encouraged to attend these trainings.
Primary end point was the change in BMI after 18 months ΔBMI. Safety outcome measures were renal and hepatic function tests, measured at baseline and every 3 months during treatment.
Tolerability was assessed by the amount of observed adverse events, and by the achieved maximum dosage levels. The reasons for dropout of participants were registered.
Other end points were change in body fat percentage measured by bio-impedance analysis using a leg-to-leg bio-impedance analysis measurement, and HbA1c after 18 months. Furthermore, change in quality of life assessed using a validated Dutch translation of the Impact of Weight on Quality of Life-Kids IWQOL-kids questionnaire, 19 , 20 and change in physical fitness assessed during validated fitness tests after 18 months were analysed.
Participants were asked to fulfil a dietary diary at baseline, 9 months and 18 months to calculate caloric intake. All participants who started treatment that is, they used at least one tablet of metformin or placebo and finished follow-up of 18 months were analysed.
As most parameters were not normally distributed, data are reported as medians with interquartile ranges. To assess the effect of metformin versus placebo after 18 months of treatment on the continuous scales, the Mann—Whitney U -test was applied.
To compare the frequencies of categorical, dichotomous data, a χ 2 -test was used. All analyses have been conducted with SPSS for Windows version In all, participants were assessed for eligibility Figure 1.
There was no difference in baseline age, sex, BMI, HbA1c and HOMA-IR between the participants lost to follow-up and participants who completed the month treatment period Supplementary Tables 1 and 2.
Baseline characteristics of the analysed participants are presented in Table 1. Overall, more girls than boys were included. In both groups, most participants were early pubertal and family history positive for obesity and diabetes mellitus was frequently reported. Median BMI at baseline was Two participants did not return any medication packages during the study.
Table 2 presents the month treatment results of metformin versus placebo; the absolute values for BMI and other parameters, as well as changes over 0—18 months are displayed. Figure 2 shows that this difference between the two groups can be explained by a decrease in ΔBMI in the metformin group during the first 6—9 months of treatment and subsequent return to baseline values, which was not observed in the placebo group.
Effect of metformin on primary end points BMI and HOMA-IR after 18 months. No significant difference was observed for ΔHOMA-IR after 18 months between both groups Table 2.
Figure 2 shows that in accordance with this lack of difference between the groups at 18 months, there is also no evidence for a difference in profile of ΔHOMA-IR over time during the study. No severe adverse advents occurred in either group.
There were no derangements of renal or hepatic function Table 3. Two out of nine participants lost to follow-up in the metformin group discontinued treatment because of adverse events.
One patient had severe nausea despite dosage reductions. The other patient suffering from abdominal pain and discomfort, was not willing to try dosage reductions and terminated study participation.
In the placebo group, no participants dropped out because of adverse events. Well-known side effects of metformin, nausea and diarrhoea, were reported in both groups during the study, but participants using metformin suffered significantly more from nausea Diarrhoea occurred in None of the participants had HbA1c values above the normal threshold after 18 months.
Effect of metformin on HbA1c and body composition after 18 months. Graphs represent median values. There was no significant change in body fat percentage Figure 3. Table 2 shows results for quality of life measured by IWQOL-kids. For all sections and the total score, there was no difference in quality of life.
Dietary diaries were not completed and returned adequately, and therefore the caloric intake could not be calculated and analysed. In this randomized, double-blinded, placebo-controlled trial in adolescents with obesity and insulin resistance, we found that assignment to the metformin group was associated with an initial decrease in BMI over the first 6—9 months of treatment after which BMI returned to baseline level, whereas BMI increased in placebo users.
Changes in body composition and HbA1c over 18 months were also in favour of metformin. In contrast, in the placebo group, a steady increase in BMI was observed over 18 months.
Beneficial effects on BMI upon short-term treatment with metformin have been reported before by Burgert et al. Upon 48 weeks of treatment, Wilson et al.
In our study, where we report on treatment effects after 18 months, the difference between metformin and placebo remained significant even though it seems that BMI values return to baseline in the metformin group. However, in the placebo group there was no evidence of a decrease in BMI Figure 2.
An intriguing question is therefore how BMI will change over time after these 18 months. Lavine et al. treated children with obesity and non-alcoholic fatty liver disease for 96 weeks with metformin.
In our study, two participants discontinued treatment and four participants received a reduced dosage because of adverse events, even though there were no serious adverse events or derangements in hepatic and renal function tests. These findings are comparable to the study of Wilson et al.
In studies where metformin was administered over 2—6 months, no severe adverse events, elevated hepatic or renal function tests, or decreased vitamin B12 were reported. Concerning vitamin B12, in our study, three participants in the metformin group had decreased vitamin B12 levels and therefore monitoring of vitamin B12 levels upon long-term use of metformin should be considered.
In all studies nausea and diarrhoea were the most frequently reported side effects. From this study, it seems that safety and tolerability of long-term metformin treatment is comparable to short-term treatment 6 months to 48 weeks , with no serious adverse events and only a small percentage of participants who do not tolerate metformin.
In the current study, participants treated with metformin were found to have an improved body composition measured by bio-impedance analysis after 18 months, with a decrease in fat mass and increase in fat-free mass compared with placebo.
In the placebo group, the change in fat-free mass was larger than the change in fat mass. The placebo group has a larger increase in height Table 2 during the 18 months; the increase in fat-free mass might be related to this increase in height.
We assume that this increase in height, and therewith in fat-free mass, is caused by a difference in pubertal stage during the study. In the metformin group an increase in fat-free mass in accordance with their increase in height over 18 months was found, without an increase in fat mass, resulting in a stable BMI.
Also in other studies, a favourable effect of metformin on body composition measured by dual-energy X-ray absorptiometry or bio-impedance analysis after 2—11 months of treatment, compared with placebo was reported.
A limitation of our study is the number of included participants. This high dropout rate illustrates the difficulties in motivating adolescents with obesity for long-term treatment and follow-up.
This difficulty is underlined by the poor attendance at physical fitness tests and by the dietary diaries, which had limited completeness and reliability.
Frequent phone calls and written reminders by the study staff did not improve the compliance. The low number of included participants and high dropout rate could have resulted in insufficient power to statistically test our hypotheses.
However, although our study has less power than anticipated, we were able to detect a significant effect of metformin on the primary outcome measure ΔBMI. For comparison, with respect to the IR outcome, other studies with sufficient power did not find an effect on IR after 6 months and 48 weeks either.
As a possible explanation for this finding, participants may not tell the truth about their fasting state during the screening. Another reason may be the large coefficient of variation that has been reported for fasting insulin.
In conclusion, long-term treatment with metformin in adolescents with obesity and insulin resistance results in a stabilization of BMI and improved body composition compared with placebo.
Therefore, metformin may be considered a safe additional therapy in combination with lifestyle intervention. Ahluwalia N, Dalmasso P, Rasmussen M, Lipsky L, Currie C, Haug E et al. Trends in overweight prevalence among , and year-olds in 25 countries in Europe, Canada and USA from to Eur J Public Health ; 25 Suppl 2 : 28— Article Google Scholar.
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Effect of weight reduction on leptin, total ghrelin and obestatin concentrations in prepubertal children. J Biol Regul Homeost Agents ; 26 1 Suppl : S95—S CAS PubMed Google Scholar. Gronbaek H, Lange A, Birkebaek NH, Holland-Fischer P, Solvig J, Horlyck A et al.
Effect of a week weight loss camp on fatty liver disease and insulin sensitivity in obese Danish children. J Pediatr Gastroenterol Nutr ; 54 : — Weight loss in obese prepubertal children: the influence of insulin resistance.
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Long term trends in oral antidiabetic drug use among children and adolescents in the Netherlands. Br J Clin Pharmacol ; 80 : — Hsia Y, Dawoud D, Sutcliffe AG, Viner RM, Kinra S, Wong IC.
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METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.
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Metformin Sennsitivity regarded as an antihyperglycaemic agent because ineulin lowers blood glucose concentrations Garden vegetable pasta type 2 non-insulin-dependent diabetes without causing overt hypoglycaemia. Its clinical efficacy sensiitvity the presence of insulin and involves several therapeutic effects. Of these effects, some are mediated via increased insulin action, and some are not directly insulin dependent. Metformin acts on the liver to suppress gluconeogenesis mainly by potentiating the effect of insulin, reducing hepatic extraction of certain substrates e. lactate and opposing the effects of glucagon. In addition, metformin can reduce the overall rate of glycogenolysis and decrease the activity of hepatic glucosephosphatase.
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Metformin vs InsulinMetformin and insulin sensitivity -
The increased cellular uptake of glucose is associated with increased glycogen synthase activity and glycogen storage. Other effects involved in the blood glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation and a reduction in hypertriglyceridaemia.
These effects reduce the energy supply for gluconeogenesis and serve to balance the glucose-fatty acid Randle cycle. Increased glucose turnover, particularly in the splanchnic bed, may also contribute to the blood glucose-lowering capability of metformin.
Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. Some other effects of metformin may result from changes in membrane fluidity in hyperglycaemic states.
Metformin therefore improves hepatic and peripheral sensitivity to insulin, with both direct and indirect effects on liver and muscle. It also exerts effects that are independent of insulin but cannot substitute for this hormone.
These effects collectively reduce insulin resistance and glucotoxicity in type 2 diabetes. Abstract Metformin is regarded as an antihyperglycaemic agent because it lowers blood glucose concentrations in type 2 non-insulin-dependent diabetes without causing overt hypoglycaemia.
Traditionally, chronic exercise reduces CVD risk by decreasing blood pressure, triglycerides TG , and inflammation Metformin is not only used to treat T2D but also it is suggested to lower CVD risk However, there are few data from randomized trials examining if metformin alters the vasculature adaptation to exercise.
From our observations of blunted insulin sensitivity following the combined treatment 32 , we studied the impact metformin would have on exercise-mediated improvements in CVD risk factors i. When metformin and exercise were combined though, blunted reductions in systolic blood pressure and CRP were observed.
These data were in line with others reporting that combining metformin with a low-fat diet and increase physical activity program had no further improvement in blood pressure Furthermore, our observations were confirmed in obese insulin resistant adolescents whereby the metformin plus lifestyle modification blunted reductions in CRP as well as fibrinogen Taken together, the metformin plus exercise therapy has strong clinical potential to oppose the reversal of chronic disease, including hypertension and metabolic syndrome.
Further work is required for elucidating the vascularture mechanism s e. Although these effects of insulin are clearly important for systemic glucose control, more recent work highlights that insulin also impacts memory, mood, and cognition 97 , Interestingly, Williams et al.
In particular, this improvement in memory was related to increased blood oxygen level-dependent BOLD signaling as measured by functional MRI fMRI during the clamp Furthermore, improved memory was best in those individuals with the highest systemic insulin sensitivity.
This suggests that declines in insulin sensitivity may contribute to brain pathology in the hypothalamus Not surprisingly, this may relate to cognitive decline , cerebral atrophy as well as low brain blood flow and metabolism across aging Additionally, this altered brain insulin action may be a key pathological factor in regulating glycemic control in individuals with obesity, T2D, aging, and Alzheimer's disease , During exercise brain glucose uptake declines in an intensity-based manner This is likely the result of increased substrate availability e.
Interestingly, the latter findings were observed in the parietal-temporal and caudate regions, which are linked to Alzheimer's disease. In either case, there remains limited data in humans with obesity or T2D confirming the effects of exercise on brain insulin sensitivity in relation to glucose metabolism.
It was shown that lifestyle modification inducing weight loss, including increased physical activity and low-fat diet, increased brain insulin sensitivity in people with obesity as assessed by intranasal insulin spray Moreover, Honkala et al.
This intensity-based effect was observed despite both exercise intensities raising whole-body insulin sensitivity. This later finding of discordance with brain and periphery insulin action following high intensity exercise on tissue-specific glucose uptake, is consistent with the observation that people with increased brain glucose uptake in response to insulin have decreased insulin-stimulated skeletal muscle glucose disposal Because exercise is known to increase skeletal muscle insulin sensitivity, it is paramount to understand the role exercise dose on affecting insulin-mediated brain glucose metabolism.
Recently, wheel running in obese rats with T2D indicated that exercise was capable of improving insulin-stimulated posterior cerebral artery vasodilation in association with nitric oxide and reduced ET-1 signaling Moreover, Ruegsegger et al.
reported that exercise improved brain insulin sensitivity of rodents fed a high-fat diet The mechanism by which exercise increased brain insulin sensitivity appears related to increased ATP and reduced ROS generation by mitochondria.
Metformin has been suggested as a potential treatment for cognitive impairment Because metformin has been shown to promote peripheral insulin sensitivity, it would be reasonable to expect an impact on the brain. A recent pilot trial was conducted whereby metformin was administered in patients with Alzheimer's disease It was reported that metformin was linked to improved learning, memory, and attention in individuals with mild cognitive impairment.
The reason metformin may improve this cognitive function in humans remains to be elucidated, but work in high-fat-fed rodents suggests that increased brain insulin sensitivity, as well as cerebral and hippocampal mitochondrial function, may play a role In addition, metformin is capable of crossing the blood-brain barrier and regulating tau phosphorylation in mouse models, thereby minimizing risk for Alzheimer's disease To date, no studies have examined how metformin in combination with exercise affects brain regulation of glycemic control.
This may be important given the collective body of literature demonstrates that metformin attenuates skeletal muscle insulin sensitivity 23 , 32 , 54 , and skeletal muscle is a key tissue proposed to secrete myokines that affect brain function and cognition Most agree that exercise or metformin therapy alone confer favorable effects on cellular pathways that regulate glycemic control across tissues for T2D and CVD risk reduction.
It now appears clear that the mechanism s by which exercise and metformin act to affect health interact on some yet to be determined pathway s that influences adaptation. Aerobic fitness i. Not surprisingly, elevations in VO 2 peak have been implicated in metabolic adaptations e.
A reason metformin could constrain gains in aerobic fitness relates to the observation that metformin partially inhibits Complex 1 of the mitochondrial electron transport system In turn, we examined the impact metformin has on VO 2 peak 10 weeks of exercise training in individuals with prediabetes This observation is consistent with new work highlighting that even acute administration of metformin raised perceptions of effort during exercise However, it is worth acknowledging that not all studies confirm that metformin decreases VO 2 peak.
In fact, some have shown metformin to raise exercise tolerance in people with coronary artery disease A possible reason metformin interacts with exercise-mediated skeletal muscle adaptation relates to lowering mitochondrial ROS generation We previously hypothesized that skeletal muscle contraction induced ROS generation is an important mediator of glucose and insulin metabolism adaptation, in part based on literature showing anti-oxidants blunt exercise health benefit Newer literature supports this idea suggesting that blunting NADPH oxidase 2 NOX2 -mediated ROS, which is responsible for GLUT-4 translocation, blunts glucose uptake during muscle contraction in both human and mouse models But, because metformin counters ROS signaling in muscle, it is possible that the post-exercise cellular signals important for mitochondrial capacity e.
This hypothesis was somewhat supported by prior work, whereby Sharoff et al. showed that metformin blunted the rise in AMPK activity during the immediate post-exercise period in insulin resistant adults, and this skeletal muscle observation directly correlated with attenuated insulin sensitivity However, new work suggests that acute metformin treatment for 4 days did not affect AMPK activity during exercise in skeletal muscle or adipose tissue of lean healthy men.
However, a novel observation was that metformin concentrations were detected in skeletal muscle, and it was proposed that longer duration e.
We recognize though that not all studies support the action of metformin to reduce complex I of the mitochondria and impact indirectly AMPK, and this is an area of much debate Interestingly, it was proposed that metformin may impact immune function in older adults following resistance training, and alleviate inflammatory mediated processes that may hinder muscle accretion in response to resistance exercise This is consistent with the notion that metformin promotes polarization from M1 pro-inflammatory macrophages to M2 anti-inflammatory macrophages 49 as well as induces autophagy to attenuate Th2 immune cell activation and inflammation However, the results of the recent MASTERS trial showed no effect of metformin on resistance training-induced inflammation in skeletal muscle, despite the observation that lean body mass gains were blunted in relation to strength following the combined therapy compared with resistance exercise training alone.
This was shown to parallel AMPK activation as well as inhibition of p70S6K1 phosphorylation an immediate target of mTOR In fact, it is important to acknowledge that there are no suggestions for altered fasting glucose or liver insulin action in response to exercise plus metformin.
Moreover, although elevated FFA levels have been detected following the combined therapy, no studies have been specifically designed to understand adipose insulin sensitivity following exercise plus metformin treatment.
Nor has there been work examining the interaction of exercise and metformin on vasculature or brain insulin sensitivity to understand the importance of blood delivery and neural control of glucose metabolism.
At this time, skeletal muscle appears to be a primary tissue regulating blood glucose, and additional cellular work is warranted to understand if these combined therapies lead to over-taxation of bioenergetic pathways that result in mal-adaptation.
This may be particularly important since new work suggests that exercise may alter the pharmacokinetics and increase the bio-availability of metformin in circulation Developing precise exercise programs for maximal glycemic control remains to be identified.
The collective literature suggests that, if anything, metformin attenuates the effects of exercise at improving insulin sensitivity at the level of skeletal muscle. Moreover, alterations in blood glucose, hypertension as well as inflammation have been noted.
While no study to date has shown blood glucose to worsen as reflected by higher blood glucose concentrations relative to the start of the combined treatment, the literature highlights that there are either null, additive, or blunted effects on glycemia.
The reason for this variability is not entirely clear but may relate to studies whereby people are habitual vs. naive metformin users or the outcome of interest.
In either case, it is clear the magnitude of benefit will vary based on what tissue or outcome is of interest. Systemic studies determining the benefit of different exercise doses as well as risk factors of people age, hypertension, dementia, T2D, etc.
co-prescribed metformin would enable individualized treatments that favor glycemic control. Further, these gains in aerobic fitness and muscle mass are not only relevant to aging men and women with or without chronic disease, but also children and adolescents.
But the effect of prescribing metformin with exercise in children and adolescents have on the rate of gain in these fitness outcomes is largely unknown in boys and girls. With emerging literature suggesting that off label or prophylactic use of metformin may be effective for weight management and obesity prevention in adolescents 54 , 71 , more children may be provided metformin and recommended to exercise.
This raises potential concern toward altered maturation growth rates and cardiometabolic risk during youth as well as then for later in life health risk compared with youth advised to exercise only with proper nutrition 54 , Thus, health care providers should be aware of these potential interactions to strike balance between current disease risk with long-term well-being.
We also recognize that people are not often prescribed only one medication, and further work is warranted to tease out the effects of multiple pharmacological agents or even dietary supplements e. in combination with exercise to gain a better understanding on glucose metabolism.
However, it is important to acknowledge that recent work has suggested that other glycemic medications, including GLP-1 agonists and SGLT-2 inhibitors, have been shown to interact with exercise — This highlights the potential for medications to interfere or add with exercise-mediated glycemic benefit.
Thus, there is potential for people to be at risk for developing T2D or cardiovascular abnormalities when co-prescribed treatments compared with those treated with exercise alone over time. Large-randomized clinical trials are critically needed to determine the effects combining exercise, with or without diet, and medications for improved evidenced-based practice.
SM wrote the majority of the review with NS providing edits. SM and NS collaborated on writing on the metformin and exercise on brain insulin sensitivity section.
NS drafted the figure with SM providing edits. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank Emily M. Heiston, Udeyvir Cheema and Anna Ballanytne for helpful discussions related to topics herein.
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Insulin resistance is a common condition jnsulin affects many individuals, Metformin and insulin sensitivity those with prediabetes Metformln type 2 diabetes. Metformin and insulin sensitivity occurs when the body's insluin become less responsive to insulin, a hormone that helps regulate blood sugar levels. Understanding insulin resistance is crucial for effective management and treatment. With Cabinet®, the 1 most loved💖 online pharmacy, all eligible prescriptions now come with:. Insulin resistance is a metabolic disorder characterized by the cells' reduced ability to respond to insulin.
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